The tumor suppressor p53 is a nuclear protein whose role in tumorigenesis is well documented, with over 31,000 citations. The importance of p53 as a tumor suppressor protein is manifested in that greater than 50% of all tumors are deficient in p53 function. Li Fraumeni Syndrome, a highly penetrant disease in which 90 percent of patients get tumors by the age of 60, is caused by genetic mutations in the p53 locus and loss of heterozygosity. p53 is a mediator of apoptosis and cell cycle arrest caused by cellular stress, such as DNA damage, hypoxia, starvation, and inappropriate expression of an oncogene. Functions of p53 are generally believed to include activating transcription of pro-apoptotic and cell cycle arrest genes, trans-repression of various cell cycle genes, binding to Bcl-XL and Bcl-2 in order to activate apoptosis at the mitochondria, and mediating DNA repair. G1 arrest or apoptosis follows once p53 is activated, depending upon the extent of cellular damage and cell type. The role of p53 in an unstressed state is still an enigma. Many groups have made various transgenic, knock in, and knock out models of p53 to determine the normal role of p53 in vivo. These models have helped us learn the role of p53 after stress and determine the effects of addition or loss of p53 to the organism. Trp53-/- (mouse p53 null) mice develop spontaneous tumors between the ages of 3-6 months and p53-null cells have a variety of abnormalities including defects in G1 arrest, apoptotic induction, and centrosome duplication. The cause of spontaneous tumorigenesis in p53 null mice remains unknown. To understand the essential post-translational modifications of p53 after stress, we generated a transgenic mouse strain, carrying a TP53 transgene (genomic human p53) including the endogenous promoter, which was backcrossed into the mouse p53-null background. In Trp53-/-/TP53 (SWAP, human p53 swapped for mouse p53), mouse embryonic fibroblasts (MEFs), human p53 is upregulated after g-irradiation and UV-irradiation, and is phosphorylated normally by murine kinases responsible for activation of p53 after stress. However, human p53 did not protect against induced carcinogenesis after either genotoxic or oncogenic stress, comparable in phenotype to p53 null mice. We found lack of transactivation of many p53-responsive genes, such as p21 and Bax, which would explain the loss of apoptotic activity and cell cycle arrest in SWAP cells. The cause of this phenomenon was due to an increase of mouse Mdm2 binding to human p53 in the cells, thus causing a lack of acetylation of p53 at Lys382. Upon suppression of Mdm2 binding to p53 using nutlin-3a, acetylation was restored and apoptosis activated. This clearly demonstrates a mechanism of apoptotic suppression via Mdm2-mediated inhibition of p53 acetylation. Surprisingly, TP53 rescues the SWAP mice from spontaneous tumorigenesis. This would suggest a novel role for p53 in the prevention of spontaneous tumorigenesis that is distinct from its role in protection from genotoxic or oncogenic stresses. Therefore, characterization of SWAP mice would be of great interest in the understanding of how p53 monitors spontaneous tumorigenesis under normal conditions. A new function of p53 in spontaneous tumorigenesis may be revealed. Recently, we have found two mechanisms of human p53 function that still remain intact in SWAP cells: p53-mediated trans-repression and control of centrosome duplication. We are currently trying to understand how these mechanisms will be able to prevent the induction of spontaneous tumorigenesis. The wildtype p53-induced phosphatase (Wip1or PPM1D) is a serine/threonine phosphatase that is transcriptionally upregulated by p53 following UV and ionizing radiation. PPM1D inhibits p53 activity indirectly through dephosphorylation and down-regulation of the p53-activating p38 MAP kinase.